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HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling.

ABSTRACT: The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic helix-loop-helix family of transcription factors, binds with high affinity to polycyclic aromatic hydrocarbons (PAH) and the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Most of the biochemical, biological, and toxicological responses caused by exposure to PAHs and polychlorinated dioxins are mediated, at least in part, by the AhR. The AhR is a client protein of Hsp90, a molecular chaperone that can be reversibly acetylated with functional consequences. The main objective of this study was to determine whether modulating Hsp90 acetylation would affect ligand-mediated activation of AhR signaling. Trichostatin A and suberoylanilide hydroxamic acid, two broad spectrum HDAC inhibitors, blocked PAH and dioxin-mediated induction of CYP1A1 and CYP1B1 in cell lines derived from the human aerodigestive tract. Silencing HDAC6 or treatment with tubacin, a pharmacological inhibitor of HDAC6, also suppressed the induction of CYP1A1 and CYP1B1. Inhibiting HDAC6 led to hyperacetylation of Hsp90 and loss of complex formation with AhR, cochaperone p23, and XAP-2. Inactivation or silencing of HDAC6 also led to reduced binding of ligand to the AhR and decreased translocation of the AhR from cytosol to nucleus in response to ligand. Ligand-induced recruitment of the AhR to the CYP1A1 and CYP1B1 promoters was inhibited when HDAC6 was inactivated. Mutation analysis of Hsp90 Lys(294) shows that its acetylation status is a strong determinant of interactions with AhR and p23 in addition to ligand-mediated activation of AhR signaling. Collectively, these results show that HDAC6 activity regulates the acetylation of Hsp90, the ability of Hsp90 to chaperone the AhR, and the expression of AhR-dependent genes. Given the established link between activation of AhR signaling and xenobiotic metabolism, inhibitors of HDAC6 may alter drug or carcinogen metabolism.

SUBMITTER: Kekatpure VD

PROVIDER: S-EPMC2658039 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling.

Kekatpure Vikram D VD Dannenberg Andrew J AJ Subbaramaiah Kotha K

The Journal of biological chemistry 20090121 12

The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic helix-loop-helix family of transcription factors, binds with high affinity to polycyclic aromatic hydrocarbons (PAH) and the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). Most of the biochemical, biological, and toxicological responses caused by exposure to PAHs and polychlorinated dioxins are mediated, at least in part, by the AhR. The AhR is a client protein of Hsp90, a molecular chaperone that can ...[more]

PMID: 19158084

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Project description:BackgroundMultiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE).MethodsAn in silico analysis was carried out to predict interactions between Ahr and potential natural ligands. The effects of a predicted interaction were examined in vitro using CD4+ T cells under T helper17 (Th17) cell-polarizing conditions and lipopolysaccharide (LPS)-stimulated macrophages. Silencing Ahr and microRNA (miR)-132 was achieved by electroporation. Myelin oligodendrocyte glycoprotein (MOG)35-55 and the adoptive transfer of encephalitogenic CD4+ T cells were used to induce EAE.ResultsMolecular docking analysis and in vitro data identified gallic acid (GA) as a novel Ahr ligand with potent activation potential. GA induced the expression of Ahr downstream genes, including cytochrome P450 family 1 subfamily A member 1 (Cyp1a1) and the miR-212/132 cluster, and promoted the formation of the Ahr/Ahr nuclear translocator (Arnt) complex. In vivo, GA-treated mice were resistant to EAE and exhibited reduced levels of proinflammatory cytokines and increased levels of transforming growth factor-β (TGF-β). Furthermore, GA reduced infiltration of CD4+CD45+ T cells and monocytes into the CNS. The anti-inflammatory effects of GA were concomitant with miR-132-potentiated cholinergic anti-inflammation and the regulation of the pathogenic potential of astrocytes and microglia. Inducing EAE by adoptive transfer revealed that CD4+ T cells were not entirely responsible for the ameliorative effects of GA.ConclusionOur findings identify GA as a novel Ahr ligand and provide molecular mechanisms elucidating the ameliorative effects of GA on EAE, suggesting that GA is a potential therapeutic agent to control inflammation in autoimmune diseases such as MS.

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HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling.

Publications

HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling.

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